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论文类型：期刊论文

发表时间：2011-12-01

发表刊物：INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES

收录刊物：Scopus、SCIE、PubMed

卷号：12

期号：12

页面范围：8961-8981

ISSN号：1422-0067

关键字：NOP agonist; N-substituted spiropiperidine analogues; 3D-QSAR; molecular docking; molecular dynamics

摘要：The nociceptin/orphanin FQ (NOP) receptor is involved in a wide range of biological functions, including pain, anxiety, depression and drug abuse. Especially, its agonists have great potential to be developed into anxiolytics. In this work, both the ligand- and receptor-based three-dimensional quantitative structure-activity relationship (3D-QSAR) studies were carried out using comparative molecular field analysis (CoMFA) and comparative molecular similarity indices analysis (CoMSIA) techniques on 103 N-substituted spiropiperidine analogues as NOP agonists. The resultant optimal ligand- based CoMSIA model exhibited Q(2) of 0.501, R-ncv(2) of 0.912 and its predictive ability was validated by using an independent test set of 26 compounds which gave R-pred(2) value of 0.818. In addition, docking analysis and molecular dynamics simulation (MD) were also applied to elucidate the probable binding modes of these agonists. Interpretation of the 3D contour maps, in the context of the topology of the active site of NOP, provided insight into the NOP-agonist interactions. The information obtained from this work can be used to accurately predict the binding affinity of related agonists and also facilitate the future rational design of novel agonists with improved activity.